Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Cancer Res. 2011 Apr 15;71(8):2978-87. doi: 10.1158/0008-5472.CAN-10-3482. Epub 2011 Apr 5.
The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA (mtDNA) replication and transcription. Disruption of TFAM results in heart failure and premature aging in mice. But very little is known about the role of TFAM in cancer development. Here, we report the identification of frequent frameshift mutations in the coding mononucleotide repeat of TFAM in sporadic colorectal cancer (CRC) cell lines and in primary tumors with microsatellite instability (MSI), but not in microsatellite stable (MSS) CRC cell lines and tumors. The presence of the TFAM truncating mutation, in CRC cells with MSI, reduced the TFAM protein level in vivo and in vitro and correlated with mtDNA depletion. Furthermore, forced overexpression of wild-type TFAM in RKO cells carrying a TFAM truncating mutation suppressed cell proliferation and inhibited RKO cell-induced xenograft tumor growth. Moreover, these cells showed more susceptibility to cisplatin-induced apoptosis due to an increase of cytochrome b (Cyt b) expression and its release from mitochondria. An interaction assay between TFAM and the heavy-strand promoter (HSP) of mitochondria revealed that mutant TFAM exhibited reduced binding to HSP, leading to reduction in Cyt b transcription. Collectively, these data provide evidence that a high incidence of TFAM truncating mutations leads to mitochondrial copy number reduction and mitochondrial instability, distinguishing most CRC with MSI from MSS CRC. These mutations may play an important role in tumorigenesis and cisplatin-induced apoptotic resistance of most microsatellite-unstable CRCs.
线粒体转录因子 A（TFAM）是线粒体 DNA（mtDNA）复制和转录所必需的。TFAM 的破坏会导致小鼠心力衰竭和早衰。但是，关于 TFAM 在癌症发展中的作用知之甚少。在这里，我们报告了在散发性结直肠癌（CRC）细胞系和具有微卫星不稳定性（MSI）的原发性肿瘤中频繁发现 TFAM 编码单核苷酸重复的移码突变，但在微卫星稳定（MSS）CRC 细胞系和肿瘤中未发现。MSI 的 CRC 细胞中 TFAM 截断突变的存在降低了体内和体外的 TFAM 蛋白水平，并与 mtDNA 耗竭相关。此外，在携带 TFAM 截断突变的 RKO 细胞中强制过表达野生型 TFAM 抑制了细胞增殖并抑制了 RKO 细胞诱导的异种移植物肿瘤生长。此外，由于细胞色素 b（Cyt b）表达增加及其从线粒体释放，这些细胞对顺铂诱导的细胞凋亡更敏感。TFAM 与线粒体重链启动子（HSP）之间的相互作用分析表明，突变 TFAM 与 HSP 的结合减少，导致 Cyt b 转录减少。总的来说，这些数据提供了证据表明 TFAM 截断突变的高发导致线粒体拷贝数减少和线粒体不稳定，将大多数具有 MSI 的 CRC 与 MSS CRC 区分开来。这些突变可能在大多数微卫星不稳定的 CRC 的肿瘤发生和顺铂诱导的细胞凋亡抵抗中发挥重要作用。
